PL97082B3 - Alpha-aminophenyl aliphatic carboxylic acids - useful as anti-inflammatory agents, analgesics and anti-mycotics[CH577480A5] - Google Patents

Alpha-aminophenyl aliphatic carboxylic acids - useful as anti-inflammatory agents, analgesics and anti-mycotics[CH577480A5] Download PDF

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PL97082B3
PL97082B3 PL1970139442A PL13944270A PL97082B3 PL 97082 B3 PL97082 B3 PL 97082B3 PL 1970139442 A PL1970139442 A PL 1970139442A PL 13944270 A PL13944270 A PL 13944270A PL 97082 B3 PL97082 B3 PL 97082B3
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mixture
acid
residue
ethyl ester
ether
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PL1970139442A
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Cibageigy Ag
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    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
    • C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
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    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/20—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/36—Oxygen or sulfur atoms
    • C07D207/40—2,5-Pyrrolidine-diones
    • C07D207/404—2,5-Pyrrolidine-diones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. succinimide
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    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/44—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members
    • C07D207/444—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5
    • C07D207/448—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. maleimide
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/46—Iso-indoles; Hydrogenated iso-indoles with an oxygen atom in position 1
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/02—Preparation by ring-closure or hydrogenation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D211/74—Oxygen atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D211/78—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
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    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/24—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Tertiary amino acids. Title cpds.: (where A Nis an alkylene-amino bicyclic gp. contg. 1-3 double bonds and 5-6 members in each ring; Ph is an opt. substd. phenylene; R1 is H or lower alkyl, and R2 is H or lower alkyl, lower alkenyl, cyclo-alkyl, cycloalkenyl, lower cycloalkylalkenyl, or lower cycloalkenyl-alkenyl). They have anti-inflammatory, analgesic and antimycotic properties. [CH577480A5]

Description

Opis patentowy opublikowano: 15.07.1978 97082 MKP C07d 27/14 Int. Cl.2 C07D 207/02 CZYTELNIA Ur.?cdu Podestowego Twórca wynalazku: Uprawniony z patentu: Ciba-Geigy AG., Bazylea (Szwajcaria) Sposób wytwarzania nowych pochodnych kwasów karboksylowych Przedmiotem wynala.zku jest sposób wytwarza¬ nia pochodnych alifatycznych kwasów a-/amino- fenylo/-karboiksylowych o wzorze 1, w którym Rj. oznacza atom wodoru, lub chloru jak i ich soli z metalami oraz soli addycyjnych z kwasami, we¬ dlug opisu patentowego nr 74 820.Zwiazki wytworzone sposobem wedlug wyna¬ lazku charakteryzuja sie cennymi wlasnosciami farmakologicznymi, zwlaszcza dzialaniem przeciw¬ zapalnym.Wlasciwosci przeciwzapalne zwiazków wedlug wynalazku moga byc wykazane doswiadczeniami przeprowadzonymi na zwierzetach, np. ssakach ta¬ kich, jak np. szczury., Wedlug metody doswiad¬ czalnej, opisanej na przyklad przez Wintera i wspólpracowników w Proc- Sos. Exptl. Biol. and Med., Tom 111, str. 544 (1962) badane zwiazki po¬ dawane szczurom w postaci wodnych roztworów albo zawiesin, zawierajacych karboksymetylocelu¬ loze lub poliglikol etylenowy, o chanakterze sub¬ stancji ulatwiajacej rozpuszczenie, za pomoca son¬ dy zoladkowej. Badania te przeprowadzono na do¬ roslych szczurach obu plci stosujac dawki dzienne okolo 0,0001—0,075 g/kg, korzystnie okolo 0,0005— —0,05 g/kg.Po uplywie okolo 1 godziny wstrzykiwano do lewej tylnej lapki zwierzecia doswiadczalnego 0,06 ml l°/o zawiesiny karageniny w wodnym roztwo¬ rze soli fizjologicznej a po uplywie 3—4 godzin porównywano objetosc i/albo wage obrzeklej le¬ wej tylnej lapki i prawej tylnej lapki. Róznice pomiedzy obydwoma konczynami porównuje sie z analogicznymi watrtosciami uzyskanymi dla nie poddawanych zabiegowi zwierzat kontrolnych. Po- równanie to sluzy za kryterium oceny przeciw¬ zapalnego dzialania badanych zwiazków.Wedlug opracowanej przez Newboulda, Brit. J.Phanmacol. Chemotherap., Tom 21, str. 127 (1963) metody pomocniczej wywolywania stanów artre- tycznych, szczury poddaje sie w stanie narkozy eterowej zabiegowi, polegajacemu na / uczuleniu wszystkich 4 lapek przez podanie 0,05 ml l°/o wodnej zawiesiny karageniny. Po 24 godzinach wstrzykuje sie pomiedzy iwaristewki naskórkia ogion- ka 0,1 ml l°/o zawiesiny Mycobacterium butyri- oum. Zwiazki wedlug wynalazku podawano w wyzej opisany sposób za pomoca sondy zoladko¬ wej w ciagu 14 dni poczawszy od 7 dnia od za¬ biegu, przy czym szczury wazono co tydzien, zas trzy razy w tygodniu okreslano liczbe oraz nate¬ zenie wtórnych ran artretycznyeh.Jak wykazano w przeprowadzonych badaniach, zwiazki wedlug wynalazku mozna stosowac jako srodki o dzialaniu przeciwzapalnym przy leczeniu objawów artretycznych i dermatopatologicznych, jak równiez jako zwiazki wyjsciowe do wytwarza¬ nia innych wartosciowych substancji, np. innych farmakologicznie czynnych zwiazków.Szczególnie wybitne wlasciwosci przeciwzapalne wykazuje kwas a-[3-chloro-4-/3-pirolinylo-l/-feny- 97082S7082 io]-propionowy i jego sole, takie jak wyzej wymie¬ nione, nietoksyczne, sole z metalami alkalicznymi, lub z metalami ziem alkalicznych i sole amonio¬ we, które w wyzej opisanych badaniach testowych, podane w dziennych dawkach 0,001—0,025 g/kg wagi ciala, wykazuja wybitne dzialanie przeciw¬ zapalne.Wedlug wynalazku zwiazki o wzorze 1, otrzy¬ muje sie w ten sposób, ze zwiazek o wzorze 2, w którym RL ma wyzej podane znaczenie, a X oznacza pierwszorzedowa grupe aminowa lub jego ester poddaje sie reakcji z ewentualnie odwodnio¬ nym glikolem o wzorze HO-A-OH, w którym sym¬ bol A oznacza dwuwartosciowa reszte butenowa-2 1,4-dwuhalogenobutenu, która lacznie z atomem aizotu twoirzy iresizte pirolinowa i/luib otrzymany zwiazek, ewentualnie estryfikuje sie lub przepro¬ wadza iw sól.Reaktywnym estrem glikolu jest np. jego odpo¬ wiedni dwuhalogenek, jiak dwuchlorek lub dwu- bromek. Reakcje te prowadzi sie zwlaszcza w obec¬ nosci srodka wiazacego wode lub kwas, jak meta¬ lu alkalicznego lub odpowiedniego alkoholanu lub weglanu.Otrzymane zwiazki mozna w znany sposób od¬ powiedni© dowolnie przeksztalcic w ramach refi- nioji podanych dla poszczególnych podstawników.Tak wiec np. otrzymany wolny kwas mozna ze- stryfiikowac za pomoca alkoholu w obecnosci srod¬ ka estryfikujacego, jak np. mocny kwas, np. kwas chlorowodorowy, kwas siarkowy lub kwas p-to- luenosulfonówy, jak i dwucykloheksylokaaabodwu- imid luib zwiazek dwuazowy, jak równiez i prze¬ prowadzic w chlorek kwasowy, np. za pomoca srodków chlorowcujacych, jak halogenki tionylu, jak np. chlorek tionylu lub halogenkami fosforu lub tlenohalogenkami fosforu, jak np. chlorki lub tlenochlorki.Otrzymany wolny kwas mozna znanyimi meto¬ dami przeprowadzac w sól, np. za pomoca reakcji ze zblizona do stechiometrycznej iloscia odpowied¬ niego czynnika solotwórozego, takiego jak amo¬ niak, aminy, lub wodorotlenku, weglanu albo kwasnego weglanu metalu alkalicznego, wzglednie metalu ziem alkalicznych.Otrzymane amonowe lub metaliczne sole tego rodzaju moga byc przeprowadzone w wolny zwia¬ zek przez traktowanie kwasem, na przyklad kwa¬ sem solnym, siarkowym lub octowym, na przy¬ klad az do osiagniecia niezbednego odczynu sro¬ dowiska.Otrzymany zwiazek zasadowy moze byc prze¬ prowadzany w kwasowa sól addycyjna, np. po¬ przez reakcje z nieorganicznym lub organicznym kwasem albo odpowiednim aruionitem i wyodreb¬ nienie utworzonej soli. Uzyskana sól addycyjna kwasu mozna przeobrazac przez traktowanie za¬ siada, amoniakiem lub wymieniaczem jonowym w formie hydroksylowej, w wolny zwiazek.Kwasowymi solami addycyjnymi, takimi jak stosowalne farmakologicznie, nietoksyczne kwaso¬ we sole addycyjne sa na przyklad zwiazki z kwa¬ sami nieorganicznymi, takimi jak kwas solny, bromowodorowy, siarkowy, fosforowy, azotowy, lub nadchlorowy, albo kwasami organicznymi, w szcze- 40 45 50 gólnosci zas z kwasami karboksylowymi lub sul¬ fonowymi, jak kwas mrówkowy, octowy, propio- nowy, bursztynowy, glikolowy, mlekowy, jablko¬ wy, winowy, cytrynowy, askorbinowy, maleinowy, hdyroksymaleinowy, pirogronowy, fenylooctowy, benzoesowy, 4-aiminobenzoesowy, antranilowy, 4- -hydroksybenzoesowy, salicylowy, aminosaiicylowy, embonowy lub nikotynowy, tfak jrówmiez metano- sulfonowy, etanosulfonowy, 2-hydroksyetanosulfo- nowy, etylenosulfonowy, benzenosulfonowy, 4-chlo- robenzenosultfonowy, 4-toluenosulfonpwy, naftale- nosulfonowy, sulfanilowy, lub cy/kloheksylosulfami- nowy. Te oraz inne sole, na przyklad pikryniany, moga byc równiez wykorzystywane dla identyfika¬ cji, jak równiez oczyszczania wolnych zwiazków; i tak, wolne zwiazki mozna przeksztalcac w ich sole, a nastepnie wydzielic je z surowej mieszani¬ ny, a potem z wyodrebnionych soli uzyskac wol¬ ne zwiazki.Z uwagi na scisly zwiazek pomiedzy nowymi zwiazkami wystepujacymi w wolnej postaci oraz w formie soli, stosowane w niniejszym opisie okreslenie ,/woine zwiazki" lub „isole" obejmuje zarówno sole jak i wolne zwiazki.Zwiazki wyjsciowe mozna wytworzyc znanymi metodami. Tak wiec np. mozna je wytworzyc, jesli w zwiazku o wzorze 3, w którym R2 ma wyzej podane znaczenie dla Rt a Xo oznacza gru¬ pe oznaczona symbolem X lub taka grupe, która mozna" latwo przeksztalcic w grupe oznaczona wy¬ zej symbolem X, np. za pomoca redukcji, tj. ozna- .. cza grupe nitrowa, zas X2 oznacza grupe dajaca sie przeprowadzic w reszte CHtRj)—R, reszty te przeksztalca sie w wyzej wymienione grupy w znany sposób.Zwiazki wedlug wynalazku wykazuja bardzo dobre wlasnosci przeciwzapalne znacznie lepsze niz porównywalne zwiazki wedlug opisu paten¬ towego nr 74 820 czego dowodzi nizej przedsta¬ wiona tablica.Zbadane zwiazki: I kwas a-[3-chloro-4-/A3-l-pirolino/-fenylo]-pro- pionowy (wedlug wynalazku), II kwas tt-^-ZS^piTolin-il-yloZ-feny^-lpropionowy (wedlug wynalazku), III kwas 2-[p-/l-pirylo/-fenylo]-propionowy (we¬ dlug opisu patentowego rur 74 820).Czynnosc przeciwzapalna zostala wykazana na podstawie testu karageninowego lapy szczurzej (patrz pierwotna strona 5, wiersz 7—17), przy czym dawke, która hamuje 50% opuchlizny lapy po¬ dano jako ED50. 60 Zwiazek I II III ED50 (mg/kg) 1,0 3,0 120,0 LD50 (mg/kg) 351 288 431 Wspól¬ czynnik terapeu¬ tyczny 351 96 3,59 Farmakologicznie uzyteczne zwiazki wedlug wy- 65 nalazku moga byc uzywane np. do wytwarzania5 97082 6 preparatów farmaceutycznych, zawierajacych efek¬ tywna dawke substancji czynnej wraz z nieor¬ ganicznymi lub organicznymi, stalymi albo plyn¬ nymi, farmaceutycznie odpowiednimi nosnikami, które nadaja sie do podawania droga pozajelito¬ wa, dojelitowa lub doimiejsoowo. Korzystnie sto¬ suje sie tabletki lub kapsulki zelatynowe, zawie¬ rajace isubstancje czynna razem ze srodkami roz¬ cienczajacymi, na przyklad laktoza, dekstroza, sa¬ charoza, mannitolem, sorbiitolem i/lub glicyna, oraz srodkami poslizgowymi, na przyklad ziemia okrzem¬ kowa, talkiem, kwasem stearowym, lub jego so¬ lami, takimi, jak stearynian magnezu albo wapnia i/lub poliglikolem etylenowym. W sklad tabletek wchodza równiez srodki wiazace, na przyklad krzemian magmazowo-gildniciwy, skrobia taka jak kukurydziana, pszeniczna, ryzowa, albo skrobia z korzenia strzalki, zelatyna, tragant, metylocelu¬ loza, sodokarboksymetyloceluloza i/lub poliwinylo- pirolidon, i — gdy to jest zadane — wypelniacze, na przyklad skrobia, agar, kwas alginowy, lub alginian sodu, lub mieszanki musujace i/lub ad¬ sorbenty, barwniki, srodki zapachowe lub slodza¬ ce.Preparatami nadajacymi sie do wstrzykiwania sa zwlaszcza izotoniozne roztwory albo zawiesiny wodne, czopki i mascie, w pierwszym rzedzie e- mulsje lub zawiesiny tluszczów. Preparaty far¬ maceutyczne moga byc wyjalawiane i/lub moga one zawierac substancje pomocnlioze, np. srodki konserwujace, stabilizujace, zwilzajace i/lub emul¬ gujace, substancje ulatwiajace rozpuszczanie, sole do regulowania cisnienia osmotyoznego i/lub bu¬ fory.Preparaty farmaceutyczne wytwarza sie wedlug znanych metod. Preparaty te zawieraja 0,1—75%, a zwlaszcza 1—50% substancji czynnej i ewentu¬ alnie kine farmakologicznie czynne substancje.Wynalazek objasniaja nizej podane pnzyklady.Przyklad I. Do mieszaniny 85,5 g chlorowo¬ dorku estru etylowego kwasu ai/4-amino-3-chloro- fenylo/-propionowego, 142 g weglanu sodu i 600 ml dwumetyloformamidu wkrapla sie przy miesza¬ niu 107 g l,4-dwubro'mobutenu-2, a nastepnie mie¬ szanine utrzymuje sie w stanie wrzenia w ciagu godzin pod chlodnica zwrotna i pozostawia na okres 16 godzin w temperaturze pokojowej. Mie¬ szanine reakcyjna przesacza sie, przesacz zateza pod zmniejszonymi cisnieniem, pozostalosc rozcie¬ ra z heksanem, przesacza i pozostalosc na saczku przemywa eterem naftowym. Przesacz zateza sie i pozostalosc, zawierajaca ester etylowy kwasu a^[3-chloro-4-/3-pirolinylo-1/-fenylo]-propionowego o wzorze 4 zadaje 280 ml 25% wodnego roztworu wodorotlenku sodu i w ciagu 8 godzin ogrzewa do wrzenia pod chlodnica zwrotna. Po ostygnieciu mieszanine rozciencza sie woda i przemywa ete¬ rem; odczyn fazy wodnej nastawia sie przy uzy¬ ciu kwasu solnego na wartosc pH 5—5,2, a na¬ stepnie ekstrahuje eterem. Ekstrakt organiczny su¬ szy sie, przesacza i zateza, a pozostalosc prze- krystalizowuje z mieszaniny benzenu i heksanu i otrzymuje kwas a-[3-chloro-4-/3-pirolinylo-l/-fe- nylo]^propionowy o wzorze 5, o temperaturze top¬ nienia 94—96°C, ?Zwiazek wyjsciowy mozna wytworzyc w naste¬ pujacy sposób: Roztwór 52 g estrtu etylowego kwa¬ su 4-nitrofenylooctowego w 350 ml mieszaniny rów¬ nych czesci dwumetyloformamidu i toluenu za- daje sie stopniowo przy mieszaniu i oziebianiu, 9,5 50% zawiesiny wodorku sodu w oleju mineral¬ nym. Po 1,5 godzinnym mieszaniu w temperatu¬ rze pokojowej wkrapla sie 26 g jodku metylu i miesza przez 16 godzin w temperaturze pokojo- io wej. Nastepnie ostroznie dodaje sie wody i ek¬ strahuje eterem; ekstrakt organiczny suszy, saczy i zageszcza. Pozostalosc rozprowadza sie w 100 ml etanolu, roztwór izaiszozepia kilkloma krysztalkami zwiazku wyjsciowego i pozostawia w niskiej tem- peratiurze. Powstajacy osad odsacza sie a przesacz zateza, pozostalosc stanowi ester etylowy kwasu • a-/4-anitrofenyio/-propaonowego.Mieszanine 50 g estru etylowego kwasu a-/4-ni- tirofenylo/-propio'nowego w i200 mil 95% uwod- nionego etanolu wysyca sie wodorem w obecnosci 0,4 g katalizatora w postaci palladu osadzonego na weglu, az do ustania reakcji przylaczania wodoru.Mieszanine saczy sie a przesacz zageszcza przez odparowanie. W ten sposób uzyskuje sie ester ety- Iowy kwasu a-/4-aminofenylo/-propionowego, któ¬ rego chlorowodprek topnieje w temperaturze 137— ^140°C.Mieszanine, sporzadzona przy mieszaniu i ozie¬ bianiu 25 g estru etylowego kwasu a-/4^aminofe- nylo/propionowego i 1100 iml bezwodnika octowego, utrzymuje sie 1 godzine w temperaturze pokojo¬ wej, a nastepnie zateza pod zmniejszonym cisnie¬ niem. Pozostalosc przekrystalizowuje sie z eteru; otrzymujac ester etylowy kwasu a-/4-acetyloami- no-fenyio/-propionowego, o temperaturze topnienia 88—90°C.Wsród mieszania i oziebiania przepuszcza sie chlor gazowy pecherzykami przez roztwór 25 g estru etylowego kwasu a-/4-acetyloaimino-fenylo/- 4o -propionowego, przy czym • przebieg chlorowania kontroluje sie za pomoca chromatografii cienko¬ warstwowej na zelu krzemowym w ukladzie hek- san-eter jak 1:4. Z chwila, gdy chromatogram nie wykasuje juz sladu substratów, mieszanine 45 odparowuje sie pod zmniejszonym cisnienieim, po¬ zostalosc rozprowadza w 150 ml etanolu i przez roztwór w ciagu 45 minut przepuszcza gazowy chlorowodór, po czym mieszanine ogrzewa sie w ciagu 15 godzin do wrzenia pod chlodnica zwrotna 50 i zageszcza. Otrzymana pozostalosc przeikrystali-- zowuje z mieszaniny etanolu i eteru i uzyskuje chlorowodorek estru etylowego kwasu a-/4-amino- -3-chlorofenylo/^propionowego, o temperaturze top¬ nienia 164—168°C. 55 Zwiazek wyjsciowy mozna równiez wytworzyc w nastepujacy sposób: Przy mieszaniu przepuszcza sie w ciagu 5,5 go¬ dziny suchy gazowy chlorowodór przez wrzaca pod chlodnica zwrotna mieszanine 5000 ml bez- 60 wodnego etanolu z 1000 g kwasu 4-aminofenylo- octowego po czym calosc miesza sie i ogrzewa do wrzenia w ciagu dalszych 4 godzin. Po 16 go¬ dzinnym oziebieniu w temperaturze 10°C miesza¬ nine przesacza sie a pozostalosc na saczku prze- 65 mywa oziebionym bezwodnym etanolem i roz,-.7 puszcza w 8000 ml wody po czym ft&eszajac do¬ daje sia 50% wodnego roztworu wodorotlenku so- flu w porcjach 50 ml az do uzyskania alkalicznego odczynu mieszaniny i miesza sie jeszcze'-w ciagu T godziny w temperaturze pokojowej. Otrzymany 5 roztwór odsacza sie i przemywa woda, otrzymu¬ jac ester etylowy kwasu 4Hamino-fenylo-octowego, o temperaturze topnienia 47—49°C.Roztwór 200 g estru etylowego kwasu 4^amkio- -fenylo-octowego w 250 ml bezwodnika octowego 10 pozostawia sie na okres 10 minut, a nastepnie mieszajac wlewa do 1500 ml mieszaniny lodu i wo¬ dy? Otrzymany osad odsacza sie i przemywa wo¬ da otrzymujac ester etylowy kwasu 4Hacetyloami- nofenyiooctowego o temperaturze topnienia 75— 15 —78°C.Roztwór 170 g estru etylowego kwasu 4^acetylo- Haimkio-fenylooctowego w 25 ml eteru mieszajac dodaje sie w ciagu 25 minut do mieszaniny utwo¬ rzonej z 20,38 g sodu, 2000 ml bezwodnego amo- 20 niafcu i kilku krysztalów dziewieciowodnego azo¬ tanu zelazowego. Nastepnie wkrapla sie w ciagu minut mieszanine 120,28 g jodku metylu i 50 ml eteru i kontynuuje mieszanie przez 1 godzine.Mieszanine zadaje sie 50 g chlorku amonu, a na- 25 stepnie zateza i pozostalosc rozprowadza w ete¬ rze i rozcienczonym wodnym roztworze wodoro¬ tlenku sodu. Roztwór zasadowy ekstrahuje sie ete¬ rem i polaczone roztwory organiczne zateza. Efek¬ tem procesu jest ester etylowy kwasu a-/4-ace- 30 tytoamdino-fenylo/HrjcropioTiowego, o temperaturze topnienia-84--86°C. Produkt o czystosci okolo 90% destyluje sie w ^estyiarce o krótkim przelocie kon¬ densatu i odbiera frakcje wrzaca pod cisnieniem 0,15 mm Hg w zakresie temperatury 170—183°C. 35 Roztwór 72 g estru etylowego kwasu aV4naoe- tyloamdinofenylo/-iproipionoiwego w 200 ml kwasu octowego traktuje sie gazowym chlorem, przepusz¬ czanymi przy mieszaniu w temperaturze 15—20°.Przebieg reakcji kontroluje sie za pomoca chro- 40 matografii cienkowarstwowej w ukladzie eter-hek- san jak 4:1. Rf produktu odpowiada wartosci 0,8, zas substancji wyjsciowej 0,51. Po ukonczeniu procesu chlorowania mieszanine zateza sie, a po¬ zostalosc poddaje destylacji. Frakcja wrzaca w 45 temperaturze 155—160° (10,7 mm Hg stanowi ester etylowy kwasu a-/4-acetyloamino-3-chlorofenylo/- ^pLiropionoiwego.Mieszanine 60 g estru etylowego kwasu a-/4- -acetyloamino-3j(^loirofenylo/-propionowego i 200 50 ml etanolu wysyca sie gazowym chlorowodorem i ogrzewa do wrzenia pod chlodnica zwrotna w ciagu 1 godziny, a nastepnie odparowuje pod zmniejiszonym cisnieniem. Pozostalosc rozprowadza sie w wodnym roztworze .wodorotlenku sodu i mie- 55 szanine ekstrahuje eterem. Wyciag eterowy zateza sie, a pozostalosc rozdziela chromatograficznie na tlenku glinu,* eluujac produkt mieszanina cyklo¬ heksanu z octanem etylu, jak 95 :5. Otrzymany tym sposobem ester etylowy kwasu -chlorofenylo/-propioinowego topnieje w tempera¬ turze 168—170°C.Przyklad II. Roztwór 25,1 g mozliwego do otrzymania metoda wedlug przykladu I kwasu d,l- a -[3-chloro-4-/3-pirolinylo-l/-fenylo]-propiono- 65 8 wego w 450 ml eteru zadaje sie, mieszajac, 17,1 g d^a-yi^naftylo/-etyloaminy; mieszanine zateza sie pod obnizonym cisnieniem, a pozostalosc pirzekry- stalizowuje siedmiokrotnie z mieszaniny etanolu i eteru. Roztwór 5 g dajacej sie uzyskac ta me¬ toda soli o temperaturze topnienia 133—135°, w minimalnej ilosci 5% wodnego roztworu wodoro^ tlenku sodu przemywa sie eterem i doprowadza do wartosci pH 5,5 za pomoca kwasu solnego, a nastepnie ekstrahuje eterem.Wyciag organiczny suszy sie, przesacza i zateza, otrzymujac w rezultacie kwas d-a-[3-chloro-4-/3- Hpirolin-il-ylo/-fenylo]-propiono(wy dla którego [a]25D = 34,8° (w etanolu).Przyklad III. Mieszanine 11,3 g czystego cis- -l,4-dwuchlorobutenu-2, 15,7 g estru etylowego kwasu a-/4-amino-ifenylo/^propionowego, 100 ml dwumetyloformamiidu i 10,6 g (weglanu sodu mie¬ szajac ogrzewa sie do wrzenia pod chlodnica zwrotna w ciagu 5 godzin, po czym pozostawia na okres 16 godzin w temperaturze pokojowej. Mie¬ szanine przesacza sie; przesacz zateza sie pod ob¬ nizonym cisnieniem, a pozostalosc, zawierajaca ester etylowy kwasu a-[4-/3-pirolinylo-l-/fenylo]- ^propionowego o wzorze 6, wprowadza sie do 25%- Howego wodnego roztworu wodorotlenku sodowego i utrzymuje w stanie wrzenia w ciagu 8 gdzin pod chlodnica zwrotna. Po ostygnieciu do mieszaniny dodaje sie wody, przemywa eterem i za pomoca kwasu solnego doprowadza wartosc pH roztworu do okolo 5. Mieszanine ekstrahuje sie eterem; wy¬ ciag organiczny osusza sie i zateza, a pozostalosc przekrysitalizowuje z etanolu. Sposobem tym otrzy¬ muje sie kwas a-4[-/3^pirolinylo-l/-fenylo]-propio- nowy o wzorze 7, o temperaturze topnienia 197— —199°.Zwiazek wyjsciowy mozna wytworzyc w na-- stepujacy sposób: roztwór 52 g estru etylowego kwasu 4-nitro-fenylo-octowego w 350 ml miesza¬ niny: dwumetyloformamid-toluen 1:1, zadaje sie stopniowo 9,5 g 50% zawiesiny wodorku sodu w oleju mineralnym. W czasie reakcji mieszanine miesza sie i oziebia. Po 1,5 godzinnym mieszaniu w temperaturze pokojowej wkrapla sie 26 g jodku metylu i mieszanine miesza w ciagu 16 godzin w temperaturze pokojowej; nastepnie mieszanine ekstrahuje sie eterem dwuimetylowym, wyciag or¬ ganiczny suszy, przesacza i zateza.Pozostalosc, wprowadza sie do 100 ml etanolu, roztwór zaszczepia kilkoma krysztalkami materia¬ lu wyjsciowego i pozostawia w niskiej tempera¬ turze. Otrzymany osad odfiltrowuje sie, a filtrat podgeszcza, tym sposoibem otrzymuje sie ester ety¬ lowy kwasu a-/4-nitrofenylo/jpropionowego.Przez mieszanine 50 g estru etylowego kwasu a-/4-nitrofenylo/^propionowego w 200 ml 95% uwodnionego etanolu przepuszcza sie wodór w obecnosci katalizatora palladowego na weglu, az do ustania reakcji i przylaczania wodoru. Miesza¬ nine filtruje sie a przesacz zateza. W efekcie do¬ daje sie ester etylowy kwasu a-/4-aminofenylo/- -propionowego, którego chlorowodorek topnieje w temperaturze 137—140°C.Przyklad IV. Do zawiesiny 4,37 g kwasu a-[3- -chloro-4-/3-pirolinylo-l/-fenylo]Hpropionowego w97082 9 10 ml wody, wkrapla sie 50°/o wodny roztwór wo¬ dorotlenku sodu az do calkowitego rozpuszczenia zawiesiny, wartosc pH wynosi okolo 12,5. Roztwór zateza sie pod cisnieniem 0,8 mm Hg, pozostalosc rozprowadza w izopropanolu, mieszanine saczy i zateza przesacz. Osad powstaly po ochlodzeniu i zaszczepieniu odsacza sie i suszy w ciagu 16 go¬ dzin w temperaturze 90°C, pod cisnieniem 0,8 mm Hg; w ten sposób otrzymuje sie sól sodowa kwasu a-/3-chloro-4-/3-pirolinylo-l/-!£enylo/HpropiiJonowiego, a temp raturze topnienia 207—210°C.Przyklad V. Uzyty w procesie zamieszczonym w przykladzie I zwiazek wyjsciowy mozna wytwa¬ rzac równiez nastepujacym sposobem: 100 ml szes- ciometylofosforoamidu mieszajac, zadaje sie w at¬ mosferze azotu 4,8 g 50% zawiesiny, wodorku so¬ du w oleju mineralnym, a nastepnie 17,1 g estru dwuetylowego kwasu a-imetylo-mialonowego, po czym ogrzewa powoli do temperatury 100° i trak¬ tuje roztworem 19,2 g 2,4-dwuohloronitrobenzenu w 20 ml szesciometylofosforoamiidu, wkriaplanym w ciagu 30 minut. Mieszanine reakcyjna utrzy¬ muje sie w ciagu 7 godzin w temperaturze 100°, a po ochlodzeniu rozciencza woda, pozostalosc mie¬ sza z woda i ekstrahuje benzenem. Wyciag orga¬ niczny przemywa sie woda, osusza, saczy i zate¬ za, a pozostalosc poddaje destylacji, frakcja wrza¬ ca w temperaturze 147—<148° pod cisnieniem 0,25 ram Hg istanowi ester idwuetylowy kwasu a-/3- -chloro-4-nitrofenylo/-a-imetylo-malonowego; odpo¬ wiedni ester dwuetylowy kwasu a-/3-chloro-4-ni- tro-fenylo/ta-etylo-malonowego wrze w tempera¬ turze 170—174° mm Hg.Przez roztwór 4 g estru dwuetyilowego kwasu a-/3-chloro-4-nitro-fenylo/-a-^metylonmalonowego w 50 ml bezwodnego etanolu przepuszcza sie przez minut pecherzykami gazowy chlorowodór po czym dodaje 0,5 g 10*/o katalizatora palladowego na weglu i wysyca mieszanine /wodorem przez 10 minut," przy poczatkowym cisnieniu 3 atmosfer.Mieszanine saczy sie, przesacz zateza pod zmniej¬ szonym cisnieniem i pozostalosc rozprowadza w */o roztworze wodorotlenku sodu, a nastepnie eks¬ trahuje eterem dwuetylowym. Wyciag organiczny osusza sie, saczy i zateza, otrzymujac w ten spo¬ sób ester dwuetylowy kwasu a-/4-airiino-3-ichloro- -fenylo/-«-!metyloHmalonojwego, którego widimo w podczerwieni wykazuje charakterystyczne pasma przy czestotliwosciach 1720, 3370 i 3460 cm-1.Mieszanine 75 g estru dwuetylowego kwasu «-/4nainmo-3-€hloro-fenyto i 150 ml 50% wodnego roztworu wodorotlenku so¬ du ogrzewa sie przez 16 godzin do wrzenia pod chlodnica zwrotna, ochladza, rozciencza woda i przemywa eterem dwuetylowym i zakwasza ste¬ zonym kwasem solnym. Pozostalosc rozprowadza sie w bezwodnym roztworze chlorowodoru w eta¬ nolu, mieszanine ogrzewa do wrzenia przez 6 go¬ dzin pod chlodnica zwrotna i zateza, a pozostalosc pirzekrystalizowuje z mieszaniny etanolu i eteru dwuetylowego. W podany sposób otrzymuje sie chlorowodorek estru etylowego kwasu a-/4-amino- -3wdhloro-fenylo/-(pro(pionowego, o temperaturze topnienia 164-^168°C.Zaistr-ziezenia patentowe 1. Sposób wytwarzania nowych pochodnych kwa¬ sów kariboksylowych o ogólnym wzorze 1, w któ¬ rym Rj oznacza atom wodoru lub atom chloru, ich estrów, oraz soli tych zwiazków wedlug pa¬ tentu nr 74 820, znamienny tym, ze zwiazek o wzo¬ rze 2, w którym R± ma wyzej podane znaczenie, a X oznacza pierwiszonzedowa grupe aminowa lub jego ester, poddaje sie reakcji ze zwiazkiem o wzo- 36 rze HO-A-OH, w którym symibol A oznacza dwu- wiartosciowa reszte butenowa-2 1,4-dwuhalogeno- butenu, tworzaca wraz z atomem azotu reszte pi- rolinowa, otrzymany wolny zwiazek przeksztalca sie w sól lub otrzymana sól przeksztalca sie w wolny zwiazek i/lub otrzymana mieszanine izo¬ merów rozdziela na poszazególne izomery. 2. Sposób wedlug zastrz. 1, znamienny tym, ze otrzymany kwas a-[3-i(^loro-4-/3^pirolinylo-li/-feny- lo^propionowy estryfikuje sie etanolem otrzymu- 40 jac ester etylowy kwasu lo-l/-fenylo]^propionowego, lub przeprowadza sie ten kwas w sól. 3. Sposób wedlug zastrz. 1, znamienny tym, ze otrzymany kwas 45 pionowy estryfikuje sie metanolem lub etanolem do estru metylowego lub etylowego lub przepro¬ wadza sie go w sól. 1597082 CHj 0 CH-C-OH CH.O klzor i Wzór 3 O II ¦CH-C-OC2H5 Cl CH3 Wzór 497082 N 0 f A—CH-C-OH I CH, Cl Wzór 5 N ci ^^-CH-C-0-C2Hs CH3 Wzór 6 o P—i ^-cH-c-0H CH, Wzór 7 PLThe patent description was published: July 15, 1978 97082 MKP C07d 27/14 Int. Cl.2 C07D 207/02 READING ROOM Ur.?cdu Platform Inventor: Authorized by the patent: Ciba-Geigy AG., Basel (Switzerland) Method for the production of new acid derivatives The subject of the invention is a process for the preparation of aliphatic α- (aminophenyl) -carboxylic acid derivatives of the formula I, in which Rj. denotes a hydrogen atom or a chlorine atom as well as their metal salts and acid addition salts according to the patent description No. 74 820. The compounds prepared according to the invention are characterized by valuable pharmacological properties, especially anti-inflammatory properties. Anti-inflammatory properties of compounds according to the invention. The invention can be demonstrated by experiments carried out on animals, for example, mammals such as, for example, rats, according to an experimental method described, for example, by Winter and colleagues at Proc-Sos. Exptl. Biol. and Med., Vol. 111, p. 544 (1962) test compounds administered to rats in the form of aqueous solutions or suspensions containing carboxymethylcellulose or polyethylene glycol having a solubilizing nature using a gastric probe. These studies were carried out in adult rats of both sexes at a daily dose of about 0.0001-0.075 g / kg, preferably about 0.0005-0.05 g / kg. After about 1 hour, the left hind paw of the experimental animal was injected 0 0.16 ml of a 100% suspension of carrageenan in an aqueous saline solution and after 3-4 hours the volume and / or weight of the swollen left hind paw and right hind paw were compared. The differences between the two limbs are compared with the corresponding values obtained with the untreated control animals. This comparison serves as a criterion for evaluating the anti-inflammatory effects of the compounds under study. According to Newbould, Brit. J.Phanmacol. Chemotherap., Vol. 21, p. 127 (1963) of the auxiliary arthritic induction method, rats are subjected to ether anesthesia by the treatment of sensitizing all 4 paws by administering 0.05 ml of 10% aqueous suspension of carrageenan. After 24 hours, 0.1 ml of 1% of the Mycobacterium butyrioum suspension is injected between the veins of the epidermis. The compounds of the invention were administered in the above-described manner by means of a gastric tube during 14 days from the 7th day after treatment, the rats were weighed weekly, and the number and severity of secondary arthritic wounds were determined three times a week. It has been shown in the studies that the compounds according to the invention can be used as anti-inflammatory agents in the treatment of arthritic and dermatopathological symptoms, as well as starting compounds for the production of other valuable substances, e.g. other pharmacologically active compounds. The anti-inflammatory properties of a-acid are particularly distinguished. [3-chloro-4- (3-pyrrolinyl-1) -phenyl-97082S7082o] -propionic acid and its salts, such as the above-mentioned non-toxic, alkali metal or alkaline earth metal salts and ammonium salts which, in the test studies described above, when given in daily doses of 0.001-0.025 g / kg body weight, show an outstanding anti-inflammatory effect. Compounds of formula I are obtained by reacting a compound of formula II, wherein RL is as defined above and X is a primary amino group, or an ester thereof is reacted with an optionally dehydrated glycol of formula HO-A -OH, in which the symbol A represents a divalent butene-2 1,4-dihalobutene residue, which together with the nitrogen atom form the pyrroline iresizte and / or the compound obtained, optionally esterified or converted into salt. The reactive ester of glycol is e.g. the corresponding dihalide, such as dichloride or di-bromide. These reactions are carried out, in particular, in the presence of a water or acid binding agent, such as an alkali metal or a suitable alkoxide or carbonate. The compounds obtained can be suitably converted in a known manner within the scope of the references given for the individual substituents. for example, the obtained free acid can be rifted with an alcohol in the presence of an esterifying agent, such as, for example, a strong acid, e.g. hydrochloric acid, sulfuric acid or p-toluenesulfonic acid, as well as dicyclohexylcaaabodimide or a diazo compound such as also and converting into the acid chloride, for example by means of halogenating agents, such as thionyl halides, such as, for example, thionyl chloride, or phosphorus halides or phosphorus oxyhalides, such as, for example, chlorides or oxychlorides. The free acid obtained can be converted into a salt by known methods. , for example by reacting with a nearly stoichiometric amount of a suitable salt forming agent such as ammonia, amines, or carbonate hydroxide, al. because of the acidic carbonate of the alkali metal or alkaline earth metal. The resulting ammonium or metal salts of this kind can be converted into a free compound by treatment with an acid, for example with hydrochloric, sulfuric or acetic acid, for example until the necessary pH is obtained. The resulting basic compound can be converted into an acid addition salt, for example, by reaction with an inorganic or organic acid or a suitable arionite and isolation of the salt formed. The obtained acid addition salt can be converted by treatment with a base, ammonia or ion exchanger in hydroxyl form, into the free compound. Acid addition salts such as pharmacologically applicable non-toxic acid addition salts are, for example, compounds with inorganic acids such as such as hydrochloric, hydrobromic, sulfuric, phosphoric, nitric or perchloric acid, or with organic acids, in particular with carboxylic or sulfonic acids such as formic, acetic, propionic, succinic, glycolic, lactic acids , apple, tartaric, lemon, ascorbic, maleic, hdyroxymaleic, pyruvic, phenylacetic, benzoic, 4-amino benzoic, anthranilic, 4-hydroxybenzoic, salicylic, aminosaiicyl, embonic or nicotinic, ethanesulfonic, 2-methane sulfonic acid hydroxyethanesulfonic, ethylenesulfonic, benzenesulfonic, 4-chlorobenzenesulfonic, 4-toluenesulfonpwy, naphthalenesulfonic, sulfanilic, or cy / clohexylsulfamic. These and other salts, for example picrates, can also be used for the identification as well as the purification of free compounds; Thus, free compounds can be converted into their salts, and then separated from the raw mixture, and then free compounds obtained from the isolated salts. Due to the close relationship between the new compounds in free and salt form, the as used herein, the term "wine compounds" or "isols" includes both the salts and the free compounds. Starting compounds can be made by known methods. Thus, for example, they can be prepared if, in a compound of formula III, in which R2 has the above meaning for Rt, and Xo is a group marked with the symbol X or such a group that can be "easily converted into a group indicated above by the symbol X , e.g. by reduction, i.e. stands for a nitro group, and X2 stands for a group that can be converted into the remainder CHtRj) -R, these residues are transformed into the above-mentioned groups in a known manner. The compounds according to the invention show very good properties anti-inflammatory significantly better than comparable compounds according to the patent description No. 74 820, as evidenced by the table below. Tested compounds: I a- [3-chloro-4- (A3-1-pyrroline / -phenyl] -propionic acid) (according to the invention), II tt-1-ZS-piTolin-yl-ylZ-phenyl-1-propionic acid (according to the invention), III 2- [p- (1-pyrryl) -phenyl] -propionic acid (according to the description Patent 74,820). The anti-inflammatory activity was demonstrated by the rat-foot carrageenan test (see original page 5, lines 7-17), ex. The dose which inhibits 50% of the paw swelling is given as the ED50. 60 Compound I II III ED50 (mg / kg) 1.0 3.0 120.0 LD50 (mg / kg) 351 288 431 Therapeutic factor 351 96 3.59 Pharmacologically useful compounds according to the invention may be used, for example, for the preparation of pharmaceutical preparations containing an effective dose of active ingredient together with inorganic or organic, solid or liquid, pharmaceutically suitable carriers which are suitable for parenteral, enteral or topical administration. Preference is given to using gelatin tablets or capsules containing the active ingredient together with diluting agents, for example, lactose, dextrose, sucrose, mannitol, sorbiitol and / or glycine, and lubricants, for example, diatomaceous earth. , talc, stearic acid or its salts, such as magnesium or calcium stearate and / or polyethylene glycol. The tablets also contain binders, for example, guild magma silicate, corn starch, wheat starch, rice starch, or arrowroot starch, gelatin, traganth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone, and Fillers, for example, starch, agar, alginic acid, or sodium alginate, or effervescent mixtures and / or adsorbents, dyes, flavors or sweeteners, are preferably injectable. In particular, isotonic solutions or aqueous suspensions are suitable for injection. suppositories and mastics, primarily fat emulsions or suspensions. Pharmaceutical preparations may be overmold and / or may contain excipients, e.g. preservatives, stabilizers, wetting and / or emulsifying agents, solubilizers, salts for regulating the osmotic pressure and / or buffers. according to known methods. These preparations contain 0.1-75%, in particular 1-5%, of active ingredient and possibly some pharmacologically active substances. The invention is illustrated by the following examples. Example 1 For a mixture of 85.5 g of ethyl ester hydrochloride of α1 / 4-Amino-3-chlorophenyl) -propionic acid, 142 g of sodium carbonate and 600 ml of dimethylformamide are added dropwise with a mixture of 107 g of 4-dibromobutene-2, and the mixture is then boiled for a long time. hours under reflux and left for 16 hours at room temperature. The reaction mixture is filtered, the filtrate is concentrated under reduced pressure, the residue is triturated with hexane, filtered and the residue on the filter is washed with petroleum ether. The filtrate is concentrated and the residue, containing α- [3-chloro-4- (3-pyrrolinyl-1 / -phenyl] -propionic acid ethyl ester of the formula IV), is mixed with 280 ml of 25% aqueous sodium hydroxide solution and heated to boiling for 8 hours. under the reflux cooler. After it has cooled, the mixture is diluted with water and washed with ether; the pH of the aqueous phase is adjusted to a value of 5-5.2 with hydrochloric acid and then extracted with ether. The organic extract is dried, filtered and concentrated, and the residue recrystallized from a mixture of benzene and hexane to give α- [3-chloro-4- (3-pyrrolinyl-1H-phenyl] -propionic acid of formula 5) , mp 94-96 ° C, the starting material can be prepared as follows: A solution of 52 g of 4-nitrophenylacetic acid ethyl ester in 350 ml of a mixture of equal parts of dimethylformamide and toluene is gradually added with stirring and cooling, 9.5% 50% sodium hydride suspension in mineral oil. After stirring for 1.5 hours at room temperature, 26 g of methyl iodide are added dropwise and the mixture is stirred for 16 hours at room temperature. Water is then carefully added and extracted with ether; the organic extract is dried, filtered and concentrated. The residue is taken up in 100 ml of ethanol, the solution is wrapped with a few crystals of the starting compound and left at a low temperature. The resulting precipitate is filtered off and the filtrate is concentrated, the remainder is • α- (4-anitrophenyl) -propaonic acid ethyl ester. A mixture of 50 g of α- (4-nitrophenyl) -propanoic acid ethyl ester in 200 mils of 95% hydrate The hydrogenated ethanol is saturated with hydrogen in the presence of 0.4 g of palladium on carbon catalyst until the addition of hydrogen ceases. The mixture is filtered and the filtrate is concentrated by evaporation. In this way, a- (4-aminophenyl) -propionic acid ethyl ester is obtained, the hydrochloride of which melts at 137 ° to 140 ° C. A mixture of 25 g of α- ethyl ester is obtained while stirring and cooling. (4-aminophenyl) propionic acid and 1100 ml acetic anhydride, are kept for 1 hour at room temperature, and then concentrated under reduced pressure. The residue is recrystallized from ether; to obtain ethyl ester of α- (4-acetylamino-phenyleth) -propionic acid, m.p. 88-90 ° C. Amidst mixing and cooling, chlorine gas is bubbled through a solution of 25 g of α- (4-acetylamino) acid ethyl ester phenyl) -4-propionic acid, the course of chlorination being monitored by thin layer chromatography on silica gel in the hexane-ether system as 1: 4. As soon as the chromatogram no longer erases the trace of the starting materials, the mixture is evaporated under reduced pressure, the residue is taken up in 150 ml of ethanol, and hydrogen chloride gas is passed through the solution for 45 minutes, then the mixture is heated to the boiling point for 15 hours under reduced pressure. reflux cooler 50 and condenser. The residue obtained is recrystallized from a mixture of ethanol and ether to give α- (4-amino-3-chlorophenyl) propionic acid ethyl ester hydrochloride, mp 164-168 ° C. 55 The starting material can also be prepared as follows: While stirring, dry hydrogen chloride gas is passed through boiling under reflux for 5.5 hours with a mixture of 5000 ml of anhydrous ethanol with 1000 g of 4-aminophenyl acetic acid, and then it is stirred and boiled for a further 4 hours. After cooling for 16 hours at 10 ° C, the mixture is filtered and the residue on the filter is washed with chilled anhydrous ethanol and dissolved in 8,000 ml of water, then 50% aqueous hydroxide solution is added. sodium in 50 ml portions until the mixture is alkaline and the mixture is stirred for a further hour at room temperature. The resulting solution is filtered off and washed with water, obtaining 4 Hamino-phenyl-acetic acid ethyl ester, m.p. 47-49 ° C. A solution of 200 g of 4-amino-phenyl-acetic acid ethyl ester in 250 ml of acetic anhydride 10 left for 10 minutes, then poured into 1500 ml of a mixture of ice and water while stirring? The resulting precipitate is filtered off and washed with water to give 4-Hacetylamino-phenylacetic acid ethyl ester, mp 75-15-78 ° C. A solution of 170 g of 4-acetyl-Haimkio-phenylacetic acid ethyl ester in 25 ml of ether is added with stirring for 25 minutes. minutes to a mixture consisting of 20.38 g of sodium, 2000 ml of anhydrous ammonium chloride and several crystals of ferric nitrate hexahydrate. Then a mixture of 120.28 g of methyl iodide and 50 ml of ether is added dropwise within minutes, and stirring is continued for 1 hour. 50 g of ammonium chloride are added to the mixture, and the mixture is gradually concentrated and the residue is taken up in ether and in dilute aqueous hydrogen solution. ¬ sodium oxide. The basic solution is extracted with ether and the combined organic solutions are concentrated. The result of the process is α- (4-acetoamdino-phenyl) HrjcropioTioic acid ethyl ester, melting point -84-86 ° C. The product, having a purity of about 90%, is distilled in a short-pass condensate ester and collected fractions boiling under a pressure of 0.15 mm Hg in the temperature range 170-183 ° C. A solution of 72 g of ethyl ester of αV4naoylamdinophenyl) in 200 ml of acetic acid is treated with gaseous chlorine, passed through with stirring at 15-20 °. The course of the reaction is monitored by thin-layer chromatography in the ether system. hexa like 4: 1. The product Rf corresponds to 0.8 and to the starting material 0.51. After the chlorination process is complete, the mixture is concentrated and the residue is distilled. The fraction boiling at 155 ° -160 ° (10.7 mm Hg is α- (4-acetylamino-3-chlorophenyl) -β-pyropionic acid ethyl ester. A mixture of 60 g of α- (4-acetylamino-3) ethyl ester ( The propionic acid and 200 ml of ethanol are saturated with gaseous hydrogen chloride and heated to reflux for 1 hour, then evaporated under reduced pressure. The residue is taken up in an aqueous sodium hydroxide solution and the mixture is extracted with ether. The ether extract is concentrated and the residue is chromatographed on alumina, eluting the product with a 95: 5 mixture of cyclohexane with ethyl acetate. The ethyl ester of chlorophenyl propionic acid thus obtained melts at 168-170 ° C. EXAMPLE II Solution of 25.1 g of d, 1- a - [3-chloro-4- (3-pyrrolinyl-1 / -phenyl] -propionic acid) in 450 ml of ether which can be obtained according to example I it is stirred, 17.1 g to ^ a-y and ^ naphthyl / ethylamine; the mixture is concentrated Not under reduced pressure and the residue pyrocrystallized seven times from a mixture of ethanol and ether. A solution of 5 g of this method of salt, mp 133-135 °, in a minimum quantity of 5% aqueous sodium hydroxide solution is washed with ether and adjusted to pH 5.5 with hydrochloric acid and then extracted with ether. The organic extract is dried, filtered and concentrated to give da- [3-chloro-4- (3-H-pyrrolin-yl) -phenyl] -propionic acid (yield for which [a] 25D = 34.8 ° (in ethanol). Example III. A mixture of 11.3 g of pure 2-cis-1,4-dichlorobutene, 15.7 g of α- (4-amino-phenyl) -propionic acid ethyl ester, 100 ml of dimethylformamide and 10, 6 g (sodium carbonate is refluxed with stirring for 5 hours, then allowed to stand at room temperature for 16 hours. The mixture is filtered; the filtrate is concentrated under reduced pressure, and the residue, containing α- [4- (3-pyrrolinyl-1- (phenyl] -β-propionic acid) ethyl ester of the formula 6, is introduced into a 25% - Hic aqueous solution of sodium hydroxide and it takes 8 hours to boil under a reflux condenser. After cooling, water is added to the mixture, washed with ether and the pH of the solution is adjusted to about 5 with hydrochloric acid. The mixture is extracted with ether; the organic extract is dried and concentrated and the residue is recrystallized from ethanol. In this way, α-4 [- (3-pyrrolinyl-1) -phenyl] -propionic acid of formula VII, mp 197 ° -199 °, is obtained. The starting compound can be prepared in the following manner: a solution of 52 g of 4-nitro-phenyl-acetic acid ethyl ester in 350 ml of a 1: 1 mixture of dimethylformamide-toluene, 9.5 g of a 50% sodium hydride suspension in mineral oil are gradually added. The mixture was stirred and cooled during the reaction. After stirring for 1.5 hours at room temperature, 26 g of methyl iodide are added dropwise and the mixture is stirred for 16 hours at room temperature; then the mixture is extracted with diethyl ether, the organic extract is dried, filtered and concentrated. The residue is added to 100 ml of ethanol, the solution is seeded with a few crystals of the starting material and left to stand at low temperature. The obtained precipitate is filtered off and the filtrate is filtered, and the?-(4-nitrophenyl) i-propionic acid ethyl ester is obtained by this method. By a mixture of 50 g of? - (4-nitrophenyl) propionic acid ethyl ester in 200 ml of 95% aqueous ethanol. hydrogen is passed through in the presence of a palladium-on-carbon catalyst until the reaction ceases and hydrogen is added. The mixture is filtered and the filtrate is concentrated. As a result, α- (4-aminophenyl) -propionic acid ethyl ester is added, the hydrochloride of which melts at 137-140 ° C. Example IV. To a suspension of 4.37 g of α- [3-chloro-4- (3-pyrrolinyl-1) -phenyl] H-propionic acid in 10 ml of water, a 50% aqueous solution of sodium hydroxide is added dropwise until complete dissolution. of the slurry, the pH value is around 12.5. The solution is concentrated under 0.8 mm Hg, the residue is taken up in isopropanol, the mixture is filtered and the filtrate is concentrated. After cooling and inoculation, the precipitate is filtered off and dried for 16 hours at 90 ° C. and 0.8 mm Hg; in this way the sodium salt of α- (3-chloro-4- (3-pyrrolinyl-1 / -! enyl) Hpropiiionic acid is obtained, with a melting point of 207-210 ° C. Example V. Used in the process of the example The starting compound can also be prepared as follows: 100 ml of hexamethylphosphoramide are mixed under nitrogen atmosphere with 4.8 g of a 50% suspension, sodium hydride in mineral oil and then 17.1 g of diethyl acid [alpha] -imethyl-mealonic acid, then slowly heated to 100 ° and treated with a solution of 19.2 g of 2,4-dihydrochloronitrobenzene in 20 ml of hexamethylphosphoramidate, which was instilled over 30 minutes. The reaction mixture is kept at 100 ° for 7 hours, and after cooling, it is diluted with water, the residue is mixed with water and extracted with benzene. The organic extract is washed with water, dried, filtered and fermented, and the residue is distilled, the fraction boiling at 147 ° to <148 ° at 0.25 bar Hg and the α-3-chloro acid diethyl ester. -4-nitrophenyl) -α-imethyl-malonic; The corresponding α- (3-chloro-4-nitro-phenyl) ta-ethyl-malonic acid diethyl ester boils at 170 ° -174 ° Hg. through a solution of 4 g. α- (3-) diethyl ester. chloro-4-nitro-phenyl) -alpha.-methylmalonic acid in 50 ml of anhydrous ethanol is bubbled through hydrogen chloride gas for minutes, then 0.5 g of 10% palladium catalyst on carbon is added and the mixture is saturated with hydrogen for 10 minutes, " at an initial pressure of 3 atmospheres. The mixture is filtered, concentrated under reduced pressure and the residue is spread in a sodium hydroxide solution and then extracted with diethyl ether. The organic extract is dried, filtered and concentrated, thus obtaining a- (4-airiino-3-chloro-phenyl) - "-! methylHmalonic acid diethyl ester, the infrared spectrum of which shows characteristic bands at frequencies 1720, 3370 and 3460 cm-1. A mixture of 75 g of diethyl acid ester" - 4-amino-3-chloro-phenyto and 150 ml of 50% aqueous sodium hydroxide solution it is heated for 16 hours under reflux, cooled, diluted water, washed with diethyl ether and acidified with concentrated hydrochloric acid. The residue is taken up in anhydrous ethanolic hydrogen chloride, the mixture is refluxed for 6 hours and concentrated, and the residue pyrocrystallized from a mixture of ethanol and diethyl ether. The hydrochloride of α- (4-amino-3-chloro-phenyl) - (pro (vertical, melting point 164- ^ 168 ° C), ethyl ester hydrochloride is obtained. carboxylic acid compounds of the general formula I, in which Rj is a hydrogen atom or a chlorine atom, their esters, and the salts of these compounds according to Patent No. 74,820, characterized in that the compound of formula 2, in which R is above given the meaning given, and X is a primary amino group or an ester thereof, is reacted with a compound of formula HO-A-OH, in which symibol A is a divalent butene-2 1,4-dihalobutene residue, forming together with the nitrogen atom of the pyrroline residue, the obtained free compound is converted into a salt or the obtained salt is converted into a free compound and / or the obtained mixture of isomers is separated into individual isomers. a- [3-i (n-roro-4- (3-pyrrolinyl-li / -phenyl-propionic acid esterified) if ethanol is used to obtain ethyl 1H-phenyl] -propionic acid, or to convert this acid into a salt. 3. The method according to p. A process as claimed in claim 1, characterized in that the obtained vertical acid is esterified with methanol or ethanol to the methyl or ethyl ester or it is converted into a salt. 1597082 CHj 0 CH-C-OH CH.O clzor i Formula 3 O II ¦CH-C-OC2H5 Cl CH3 Formula 497082 N 0 f A — CH-C-OH I CH, Cl Formula 5 N ci ^^ - CH- C-O-C2Hs CH3 Formula 6 o P — i ^ -cH-c-OH CH, Formula 7 PL

PL1970139442A 1969-07-18 1970-03-16 Alpha-aminophenyl aliphatic carboxylic acids - useful as anti-inflammatory agents, analgesics and anti-mycotics[CH577480A5] PL97082B3 (en)

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